United States Patent [19]
`Mathvink et al.
`
`US006011048A
`[11] Patent Number:
`[45] Date of Patent:
`
`6,011,048
`Jan. 4, 2000
`
`[54] THIAZOLE BENZENESULFONAMIDES AS
`gggglggggoggggemw 0F
`
`[75] Inventors: Robert J. Mathvink, Red Bank;
`Emma R. Parmee, Highland Park;
`Samuel Tolman, Jersey City; Ann E.
`Weber, Scotch Plains, all of N].
`
`[73] Assignee: Merck 8‘ C0‘, Inc-> RahWay> N~J~
`
`[60]
`
`[21] Appl. No.: 09/007,363
`.
`[22]
`Flled:
`Jan‘ 15’ 1998
`Related US‘ Application D ata
`Provisional application NO‘ 60/036 760 Jan‘ 28 1997'
`’
`’
`’
`Int. Cl.7 ....................... .. C07D 417/10; A61K 31/44
`[51]
`[52] US. Cl. ..................... .. 514/342; 546/269.7; 546/256;
`514/333
`[58] Field of Search ........................ .. 514/342; 546/2697
`
`[56]
`
`References Cited
`
`U'S' PATENT DOCUMENTS
`
`FOREIGN PATENT DOCUMENTS
`.
`0
`O 611 003 8/1994 European Pat. Off. .
`W0 95 29159 11 1995 WIPO .
`/
`/
`Primary Examiner—Jane Fan
`Attorney, Agent, or Firm—Mollie M. Yang; David L. Rose
`[57]
`ABSTRACT
`
`ThiaZole substituted benZenesulfonamides are [33 adrenergic
`receptor agonists With very little [31 and [32 adrenergic
`receptor activity and as such the compounds are capable of
`increasin li ol sis and ener
`eX enditure in cells. The
`compoun?s tphug have POIGHIgZCIlVIlJIY in the treatment of
`Type II diabetes'and obesity. The compounds can also be
`used to loWer triglyceride levels and cholesterol levels or
`raise high density lipoprotein levels or to decrease gut
`motility. In addition, the compounds can be used to reduced
`neurogenic in?ammation or as antidepressant agents. The
`compounds are prepared by coupling an aminoalkylphenyl
`sulfonamide With an appropriately substituted epoXide
`Compositions and methods for the use of the compounds in
`the treatment of diabetes and obesity and for loWering
`triglyceride levels and cholesterol levels or raising high
`density lipoprotein levels or for decreasing gut motility are
`
`9/1995 Fisher et a1. .......................... .. 546/130
`5,451,677
`5,561,142 10/1996 Fisher et a1. ..
`514/312
`5,705,515
`1/1998 Fisher et al. .......................... .. 514/365
`
`also disclosed
`
`10 Claims, N0 Drawings
`
`SAWAI EX. 1010
`Page 1 of 21
`
`

`

`1
`THIAZOLE BENZENESULFONAMIDES AS
`[33 AGONISTS FOR TREATMENT OF
`DIABETES AND OBESITY
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This application is based on, and claims priority from,
`provisional application No. 60/036,760 ?led Jan. 28, 1997.
`
`BACKGROUND OF THE INVENTION
`
`10
`
`6,011,048
`
`2
`Recently, assays have been developed Which more accu
`rately predict the effects that can be expected in humans.
`These assays utiliZe cloned human [33 receptors Which have
`been expressed in Chinese hamster ovary cells. See Emorine
`et al, Science, 1989, 245:1118—1121; Liggett, Mol.
`Pharmacol., 1992, 42:634—637; and Grannemann et al.,
`Mol. Pharmacol., 1992, 42: 964—970. The agonist and
`antagonist effects of the various compounds on the culti
`vated cells provide an indication of the antiobesity and
`antidiabetic effects of the compounds in humans.
`
`[3-Adrenoceptors have been subclassi?ed as [31 and [32
`since 1967. Increased heart rate is the primary consequence
`
`US. Pat. No. 5,451,677 discloses selective [33 agonists of
`the formula:
`
`(RIL.
`
`.
`
`of [31-receptor stimulation, While bronchodilation and
`smooth muscle relaxation typically result from [32 stimula
`tion. Adipocyte lipolysis Was initially thought to be solely a
`[31-mediated process. HoWever, more recent results indicate
`that the receptor mediating lipolysis is atypical in nature.
`These atypical receptors, later called [33-adrenoceptors, are
`found on the cell surface of both White and broWn adipocytes
`Where their stimulation promotes both lipolysis (breakdown
`of fat) and energy expenditure.
`Early developments in this area produced compounds
`With greater agonist activity for the stimulation of lipolysis
`([33 activity) than for stimulation of atrial rate ([31) and
`tracheal relaxation
`These early developments disclosed
`in AinsWorth et al., US. Pat. Nos. 4,478,849 and 4,396,627,
`Were derivatives of phenylethanolamines.
`Such selectivity for [33-adrenoceptors could make com
`pounds of this type potentially useful as antiobesity agents.
`In addition, these compounds have been reported to shoW
`antihyperglycemic effects in animal models of non-insulin
`dependent diabetes mellitus.
`A major draWback in treatment of chronic diseases With
`[33 agonists is the potential for stimulation of other
`[3-receptors and subsequent side effects. The most likely of
`these include muscle tremor ([32) and increased heart rate
`([31). Although these phenylethanolamine derivatives do
`possess some [33 selectivity, side effects of this type have
`been observed in human volunteers. It is reasonable to
`expect that these side effects resulted from partial [31 and/or
`[32 agonism.
`More recent developments in this area are disclosed in
`AinsWorth et al., US. Pat. No. 5,153,210, Caulkett et al.,
`US. Pat. No. 4,999,377, Alig et al., US. Pat. No. 5,017,619,
`Lecount et al., European Patent 427480 and Bloom et al.,
`European Patent 455006.
`Even though these more recent developments purport to
`describe compounds With greater [33 selectivity over the [31
`and [32 activities, this selectivity Was determined using
`rodents, in particular, rats as the test animal. Because even
`the most highly selective compounds, as determined by
`these assays, still shoW signs of side effects due to residual
`[31 and [32 agonist activity When the compounds are tested in
`humans, it has become apparent that the rodent is not a good
`model for predicting human [33 selectivity.
`
`US. Pat. No. 5,561,142 published Nov. 2, 1995 discloses
`selective [33 agonists of the formula
`
`25
`
`30
`
`35
`
`Compounds of the present invention that are Within the
`generic disclosure of US. Pat. No. 5,561,142 represent a
`novel selection thereof.
`
`SUMMARY OF THE INVENTION
`
`The instant invention is concerned With thiaZole substi
`tuted benZenesulfonamides Which are useful as antiobesity
`and antidiabetic compounds. Thus, it is an object of this
`invention to describe such compounds. It is a further object
`to describe the speci?c preferred stereoisomers of the sub
`stituted sulfonamides. A still further object is to describe
`processes for the preparation of such compounds. Another
`object is to describe methods and compositions Which use
`the compounds as the active ingredient thereof. Further
`objects Will become apparent from reading the folloWing
`description.
`
`DESCRIPTION OF THE INVENTION
`
`The present invention provides compounds having the
`formula I:
`
`OH
`
`H
`
`/
`
`40
`
`45
`
`55
`
`60
`
`65
`
`SAWAI EX. 1010
`Page 2 of 21
`
`

`

`6,011,048
`
`3
`-continued
`
`(12) COZRZ;
`R2 is
`(1) hydrogen,
`(2) C1—C1O alkyl optionally substituted With up to 5
`groups selected from
`(a) hydroxy,
`(b) halogen,
`(c) CO2R4,
`(d) S(O)n-C1—C1O alkyl, Where n is 0 to 2,
`(e) C3—C8 cycloalkyl,
`(f) C1—C1O alkoxy, and
`(g) Aoptionally substituted With up to 5 groups selected
`from halogen, C1—C1O alkyl and C1—C1O alkoxy,
`(3) C3—C8 cycloalkyl, or
`(4) A optionally substituted With up to 5 groups selected
`from
`(a) halogen,
`(b) nitro,
`(c) oxo,
`(d) NR4R4,
`(e) C1—C1O alkoxy,
`(f) S(O)n-C1—C1O alkyl Where n is 0 to 2, and
`(g) C1—C1O alkyl optionally substituted With up to 5
`groups selected from hydroxy, halogen, CO2R4,
`S(O)n-C1—C1O alkyl, Where n is 0 to 2, C3—C8
`cycloalkyl, C1—C1O alkoxy, and A optionally substi
`tuted With up to 5 groups selected from halogen,
`C1—C1O alkyl and C1—C1O alkoxy;
`
`R3 is
`(1) R2 or
`(2) NRZRZ;
`R4is
`(1) H, or
`Q
`C1—C1O alkyl;
`1s
`
`(1) N(R2),
`(2) O or
`(3) S(O)n, and n is 0 to 2;
`Q‘ is
`(1) N(R2),
`(2) O or
`(3) a bond; or
`a pharrnaceutically acceptable salt thereof, or a prodrug
`thereof.
`One subset of compounds of formula I provides corn
`pounds Wherein
`X is
`(1) a bond,
`(2) CH2
`(3) CHZO, Wherein C is attached to thiaZole, and O is
`attached to A;
`Another subset of compounds of formula I provides
`cornpounds Wherein
`R1 is
`(1) C1—C1O alkyl optionally substituted With up to 5
`halogens;
`(2) halogen,
`(3) QR2,
`(4) Q‘COR3,
`(5) Phenyl;
`R2 is
`(1) hydrogen,
`(2) C1—C1O alkyl optionally substituted With up to 5
`halogens;
`
`10
`
`20
`
`25
`
`wherein
`X is
`(1) a bond,
`(2) C1—C3 alkylene, optionally substituted With 1 or 2 1
`groups selected from methyl and halogen,
`(3) C1—C3 alkylene Wherein said alkylene contains an
`oxygen, optionally substituted With 1 or 2 groups
`selected from methyl and halogen;
`In is
`0 to 5;
`A is
`(1) phenyl,
`(2) a 5 or 6-rnernbered heterocyclic ring with from 1 to 4
`heteroatorns selected from oxygen, sulfur and nitrogen,
`(3) a benZene ring fused to a C5—C1O carbocyclic ring,
`(4) a 5 or 6-rnernbered heterocyclic ring with from 1 to 4
`heteroatorns selected from oxygen, sulfur and nitrogen
`fused to a 5 or 6-rnernbered heterocyclic ring with from
`1 to 4 heteroatorns selected from oxygen, sulfur and
`nitrogen, or
`(5) a 5 or 6-rnernbered heterocyclic ring with from 1 to 4
`heteroatorns selected from oxygen, sulfur and nitrogen
`fused to a C5—C1O carbocyclic ring;
`R1 is
`1C1C1Olkylp' lly b' d 'hp 5
`o t1ona
`a
`—
`su st1tute Wit u to
`groups selected from
`(a) hydroxy,
`(b) halogen,
`(c) cyano,
`(d) QR2,
`(e) C3—C8 cycloalkyl,
`(f) Aoptionally substituted With up to 5 groups selected
`from halogen, C1—C1O alkyl and C1—C1O alkoxy,
`(g) Q‘cORi
`(h) S(O)nR3, Where n is 0 to 2,
`(i) NR2SO2R3,
`NRZCOZRZ, and
`(k) COZRZ,
`(2) C3—C8 cycloalkyl,
`(3) oxo,
`(4) halogen,
`(5) cyano,
`(6) QR2,
`(7) S(O)nR3, Where n is 0 to 2,
`(8) Q‘COR3,
`(9) NR2SO2R3,
`(10) NRZCOZRZ,
`(11) A optionally substituted With up to 5 groups inde
`pendently selected from
`(a) R2,
`(b) QR2,
`(c) halogen, and
`(d) oxo; or
`
`35
`
`45
`
`55
`
`SAWAI EX. 1010
`Page 3 of 21
`
`

`

`6,011,048
`
`R3 is
`(1) C1—C1O alkyl; and
`Q is
`(1) Q.
`There is one subset of compounds of formula I Wherein
`the thiaZolyl moiety is attached to the benZenesulfonamide
`moiety via the carbon at the 2 position (C2) of the thiaZole
`ring. There is another subset of compounds of formula I
`Wherein the thiaZolyl moiety is attached to X, or Where X is
`a bond, directly to Avia the carbon at the 2 position of the
`thiaZole ring. Preferably, either the benZenesulfonamide
`moiety or X (or A, if X is a bond) is attached to the C2 of
`the thiaZole ring, and the other to the C4 positions of the
`thiaZole ring.
`Another subset of compounds of formula I provides
`compounds Wherein A is selected from phenyl, naphthyl, a
`5 or 6-membered heterocyclic ring With from 1 to 4 het
`eroatoms selected from oxygen, sulfur and nitrogen fused to
`a benZene ring, and a 5 or 6-membered heterocyclic ring
`With from 1 to 4 heteroatoms selected from oxygen, sulfur
`and nitrogen. Preferably, A is selected from phenyl,
`naphthyl, thienyl, pyridinyl, benZothienyl, quinolinyl,
`indolyl, and benZofuranyl.
`In a preferred embodiment of compounds of formula I
`X is
`(1) a bond,
`(2) CH2,
`(3) CHZO, Wherein C is attached to thiaZole, and O is
`attached to A;
`m is
`0 to 5;
`A is
`(1) phenyl,
`(2) a 5 or 6-membered heterocyclic ring With from 1 to 4
`heteroatoms selected from oxygen, sulfur and nitrogen,
`(3) a benZene ring fused to a C5—C1O carbocyclic ring,
`(4) a 5 or 6-membered heterocyclic ring With from 1 to 4
`heteroatoms selected from oxygen, sulfur and nitrogen
`fused to a 5 or 6-membered heterocyclic ring With from
`1 to 4 heteroatoms selected from oxygen, sulfur and
`nitrogen, or
`(5) a 5 or 6-membered heterocyclic ring With from 1 to 4
`heteroatoms selected from oxygen, sulfur and nitrogen
`fused to a C5—C1O carbocyclic ring;
`R1 is
`(1) C1—C1O alkyl optionally substituted With up to 5
`halogens;
`(2) halogen,
`(3) QR2,
`(4) Q‘COR3,
`(5) Phenyl;
`R2 is
`(1) hydrogen,
`(2) C1—C1O alkyl optionally substituted With up to 5
`halogens;
`R3 is
`(1) C1—C1O alkyl; and
`Q is
`(1) O; or
`a pharmaceutically acceptable salt thereof.
`In a more preferred embodiment are compounds of for
`mula I Wherein
`X is
`
`10
`
`15
`
`25
`
`35
`
`45
`
`55
`
`65
`
`(1) a bond,
`
`(3) CHZO, Wherein C is attached to thiaZole, and O is
`attached to A;
`m is
`0 to 5;
`A is
`(1) phenyl,
`(2) a 5 or 6-membered heterocyclic ring With from 1 to 4
`heteroatoms selected from oxygen, sulfur and nitrogen,
`(3) naphthyl, or
`(4) a 5 or 6-membered heterocyclic ring With from 1 to 4
`heteroatoms selected from oxygen, sulfur and nitrogen
`fused to a benZene ring;
`R1 is
`(1) C1—C1O alkyl optionally substituted With up to 5
`halogens;
`(2) halogen,
`(3) QRZ,
`(4) Q‘COR3,
`(5) Phenyl;
`R2 is
`(1) hydrogen,
`(2) C1—C1O alkyl optionally substituted With up to 5
`halogens;
`R3 is
`(1) C1—C1O alkyl; and
`Q is
`(1) O; and
`either the benZenesulfonamide moiety or X (or A, if X is a
`bond) is attached to the C2 of the thiaZole ring, and the other
`to the C4 positions of the thiaZole ring; or
`a pharmaceutically acceptable salt thereof.
`Compounds of the present invention that are Within the
`generic structure disclosed in Us. Pat. No. 5,561,142 rep
`resent a novel selection thereof. The present compounds are
`potent [33 agonists, and have improved oral bioavailability in
`animals.
`Representative antiobesity and antidiabetic compounds of
`the present invention include the folloWing:
`1. N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]
`phenyl]-4-[4-(2-naphthylmethyl)thiaZol-2-yl]
`benZenesulfonamide;
`2. N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-[4-(tri?uoromethyl)phenyl]thiaZol-2-yl]
`benZenesulfonamide;
`3. N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-[4-(tri?uoromethoxy)phenyl]thiaZol-2-yl]
`benZenesulfonamide;
`4. N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(3,4-di?uorophenylmethyl)thiaZol-2-yl]
`benZenesulfonamide;
`5. N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(3-pyridyl)thiaZol-2-yl]
`benZenesulfonamide;
`6. N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(4-?uorophenylmethyl)thiaZol-2-yl]
`benZenesulfonamide;
`7. N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(3,4-di?uorophenyl)thiaZol-2-yl]
`benZenesulfonamide;
`8. N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-[4-(tri?uoromethyl)phenylmethyl]thiaZol
`2-yl]benZenesulfonamide;
`
`SAWAI EX. 1010
`Page 4 of 21
`
`

`

`6,011,048
`
`8
`28. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(2,4-dichlorophenyl)thiaZol-2-yl]
`benZenesulfonamide;
`29. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-[2-(tri?uoromethyl)phenyl]thiaZol-2-yl]
`benZenesulfonamide;
`
`7
`9. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(2-pyridyl)thiaZol-2-yl]
`benZenesulfonamide;
`10. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-[1 -(2-phenyl)ethyl]thiaZol-2-yl]
`benZenesulfonamide;
`11. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(4-?uorophenyl)thiaZol-2-yl]
`benZenesulfonamide;
`12. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(2-naphthyl)thiaZol-2-yl]
`benZenesulfonamide;
`13. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(3,4,5-tri?uorophenyl)thiaZol-2-yl]
`benZenesulfonamide;
`14. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(4-heXylphenyl)thiaZol-2-yl]
`benZenesulfonamide;
`15. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-[4-(tri?uoromethoXy)phenylmethyl]thiaZol
`2-yl]benZenesulfonamide;
`16. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-[4-(tri?uoromethoXy)phenoXymethyl]
`thiaZol-2-yl]benZenesulfonamide;
`17. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(2-benZo[b]thienyl)thiaZol-2-yl]
`benZenesulfonamide;
`18. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(3-quinolinyl)thiaZol-2-yl]
`benZenesulfonamide;
`19. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(6-quinolinyl)thiaZol-2-yl]
`benZenesulfonamide;
`20. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(2-benZo[b]furyl)thiaZol-2-yl]
`benZenesulfonamide;
`21. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(3-indolyl)thiaZol-2-yl]
`benZenesulfonamide;
`22. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(2,4-di?uorophenyl)thiaZol-2-yl]
`benZenesulfonamide;
`23. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(3,5-di?uorophenyl)thiaZol-2-yl]
`benZenesulfonamide;
`24. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-[4-(1,1-dimethylethyl)phenyl]thiaZol-2-yl]
`benZenesulfonamide;
`25 . N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(2,3-di?uorophenyl)thiaZol-2-yl]
`benZenesulfonamide;
`26. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-[3-(tri?uoromethyl)phenyl]thiaZol-2-yl]
`benZenesulfonamide;
`27. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-[4-(di?uoromethyl)phenyl]thiaZol-2-yl]
`benZenesulfonamide;
`
`15
`
`25
`
`45
`
`32. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-[2,4-bis(tri?uoromethyl)phenyl]thiaZol-2
`yl]benZenesulfonamide;
`33. N-[4-[2-[[2-HydroXy-2-(pyridin-3-yl)ethyl]amino]
`ethyl]phenyl]-4-[5-(4-?uorophenyl)thiaZol-2-yl]
`benZenesulfonamide;
`34. N-[4-[2-[[2-HydroXy-2-(pyridin-3-yl)ethyl]amino]
`ethyl]phenyl]-4-[2-(4-tri?uoromethylphenyl)thiaZol-4
`yl]benZenesulfonamide;
`35. N-[4-[2-[[2-HydroXy-2-(pyridin-3-yl)ethyl]amino]
`ethyl]phenyl]-4-[2-(4-tri?uoromethylphenyl)thiaZol-5
`yl]benZenesulfonamide;
`36. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(4-phenylphenyl)thiaZol-2-yl]
`benZenesulfonamide;
`37. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(3,4-dihydroXyphenyl)thiaZol-2-yl]
`benZenesulfonamide;
`38. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(4-hydroXyphenyl)thiaZol-2-yl]
`benZenesulfonamide;
`39. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(4-acetoXyphenyl)thiaZol-2-yl]
`benZenesulfonamide;
`40. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[4-(4-acetamidophenyl)thiaZol-2-yl]
`benZenesulfonamide;
`41. N-[4-[2-[[2-hydroXy-2-(pyridin-3-yl)ethyl]amino]ethyl]
`phenyl]-4-[2-(4-tri?uoromethoXyphenyl)thiaZol-4-yl]
`benZenesulfonamide.
`The compounds of the instant invention all have at least
`one asymmetric center as noted by the asterisk in structural
`Formula I. Additional asymmetric centers may be present on
`the molecule. Each such asymmetric center Will produce tWo
`optical isomers and it is intended that all such optical
`isomers, as separated, pure or partially puri?ed optical
`isomers or racemic miXtures thereof, be included Within the
`ambit of the instant invention. In the case of the asymmetric
`center represented by the asterisk in Formula I, it has been
`found that the compound in Which the hydroXy substituent
`is above the plane of the structure, as seen in Formula Ic, is
`more active and thus more preferred over the compound in
`Which the hydroXy substituent is beloW the plane of the
`structure.
`The folloWing stereospeci?c structure represents the pre
`ferred stereoisomers of the instant invention:
`
`SAWAI EX. 1010
`Page 5 of 21
`
`

`

`6,011,048
`
`10
`
`The thiaZolyl moiety is numbered as follows:
`
`Throughout the instant application, the following terms
`have the indicated meanings:
`“Alkylene” means —(CH2) — Where p is the designated
`carbon number; one or tWo ofPthe hydrogen may be option
`ally replaced by methyl or halogen. Where the optionally
`substituted alkylene contains an oxygen, the oxygen may be
`at either end of the alkylene chain, or it may be embedded
`Within the chain. Examples include OCH2, CHZO,
`CHZOCHZ, C(CH3)2O, etc.
`The alkyl groups speci?ed above are intended to include
`those alkyl groups of the designated length in either a
`straight or branched con?guration. Exemplary of such alkyl
`groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,
`tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
`The alkoxy groups speci?ed above are intended to include
`those alkoxy groups of the designated length in either a
`straight or branched con?guration. Exemplary of such
`alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy,
`butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy,
`hexoxy, isohexoxy and the like.
`The term “halogen” is intended to include the halogen
`atoms ?uorine, chlorine, bromine and iodine.
`The term “carbocyclic ring” is intended to include both
`aromatic and nonaromatic rings containing only carbon
`atoms. Thus, a benZene ring fused to a C5—C1O carbocyclic
`ring, includes naphthyl, tetrahydronaphthyl, indanyl and
`indenyl. A5 or 6-membered heterocyclic ring With from 1 to
`4 heteroatoms selected from oxygen, sulfur and nitrogen
`fused to a C5—C1O carbocyclic ring includes benZene fused
`to a heterocyclic ring as Well as a non-aromatic carbocyclic
`ring fused to a heterocyclic ring. The carbocyclic ring
`preferably is C5—C7.
`A 5 and 6-membered heterocyclic ring, Whether isolated
`or as a part of a fused ring system, is intended to include
`aromatic and unsaturated non-aromatic heterocycles; and
`Where the heterocycle is part of a fused ring, at least one of
`the rings is aromatic. Examples of a 5 or 6-membered ring
`include pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl,
`imidaZolyl, thiaZolyl, thiadiaZolyl, tetraZolyl, oxadiaZolyl,
`oxaZolyl, imidaZolidinyl, pyraZolyl, isoxaZolyl. Examples of
`a benZene ring fused to a 5 or 6-membered heterocyclic ring
`include benZothiadiaZolyl, indolyl, indolinyl,
`benZodioxolyl, benZodioxanyl, benZothiophenyl,
`benZofuranyl, benZimidaZolyl, benZoxaZinyl,
`benZisoxaZolyl, benZothiaZolyl, 2,3-dihydrobenZofuranyl,
`quinolinyl, benZotriaZolyl, benZoxaZolyl, 1,2,3,4
`
`K7
`
`S
`
`:
`
`(R511.
`
`15
`
`25
`
`35
`
`45
`
`55
`
`tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl.
`Examples of a 5 or 6-membered heterocyclic ring fused to
`a 5 or 6-membered heterocyclic ring include purinyl, furo
`pyridine and thienopyridine. Examples of a 5 or
`6-membered heterocyclic ring fused to a non-aromatic car
`bocyclic ring include tetrahydrobenZothiaZolyl, 5,6,7,8
`tetrahydroquinolinyl, 2,3-cyclopentenopyridyl, 4,5,6,7
`tetrahydroindolyl, 5,6,7,8-tetrahydroisoquinolyl, 5,6,7,8
`tetrahydroquinoxalinyl.
`The term “composition”, as in pharmaceutical
`composition, is intended to encompass a product comprising
`the active ingredient(s), and the inert ingredient(s) that make
`up the carrier, as Well as any product Which results, directly
`or indirectly, from combination, complexation or aggrega
`tion of any tWo or more of the ingredients, or from disso
`ciation of one or more of the ingredients, or from other types
`of reactions or interactions of one or more of the ingredients.
`Accordingly, the pharmaceutical compositions of the present
`invention encompass any composition made by admixing a
`compound of the present invention and a pharmaceutically
`acceptable carrier.
`Throughout the instant application, When reference is
`made to “compounds of Formula I” it is meant to include,
`unless otherWise speci?ed, pharmaceutically acceptable
`salts and prodrugs thereof. Prodrugs are derivatives of
`compounds of Formula I that are transformed in vivo to the
`active drug molecule; prodrugs include derivatives of free
`hydroxy, amino or carboxylic groups such as esters, ethers,
`amides, carbonates, carbamates, and N-alkyl derivatives.
`Speci?c examples of prodrugs of compounds of Formula I
`include: (a) derivation of the secondary amine such as
`N-alkylation (methyl, ethyl, isopropyl and 2-methoxyethyl),
`and N-acylation (l-pyrrolidinylacetyl, 4-morpholinylacetyl,
`(1-acetoxy)ethoxycarbonyl, and dimethylaminoacetyl); (b)
`derivation of the secondary hydroxy such as O-alkylation
`(ethyl) and O-acylation (acetyl, t-butoxycarbonyl, benZoyl,
`cyclopropylcarbonyl); and (c) the vicinally positioned sec
`ondary amine and secondary hydroxy taken together form a
`group of the formula
`
`0
`
`w
`
`Wherein U and V are independently a bond, carbonyl,
`methylene, CH(OH) or C(OH)(CH3). Prodrugs of the above
`described types may be readily prepared from compounds of
`Formula I using methods Well knoW to persons skilled in the
`art.
`Certain of the above de?ned terms may occur more than
`once in the above formula and upon such occurrence each
`
`65
`
`SAWAI EX. 1010
`Page 6 of 21
`
`

`

`6,011,048
`
`11
`term shall be de?ned independently of the other; thus for
`example, NRZR2 may represent NH2, NHCH3, N(CH3)
`CH2CH3, and the like.
`The compounds (I) of the present invention can be
`prepared as described in the following schemes. ThiaZoles
`Ia, Ib and Ic are prepared via the HantZsch thiaZole synthesis
`(Sainsbury, M. In “Rodd’s Chemistry of Carbon
`Compounds”, Coffey, S., Ausell, M. F., Eds.; Elsevier:
`Amsterdam, 1986; Vol. IV C, 399—455) from the appropriate
`thioamide and 2-halocarbonyl derivative. As illustrated in
`
`12
`aniline derivative 5 (Fisher, et. al., US. Pat. No. 5,561,142,
`Oct. 1, 1996) is treated With sulfonyl chloride 4, and a base
`such as pyridine in an anhydrous solvent such as dichlo
`romethane or chloroform for 0.5 to 24 hours at temperatures
`of —20 to 50° C., preferably 0° C., folloWed by removal of
`the protecting group With, in the case of a tert
`butylcarbamate, acid such as tri?uoroacetic acid or metha
`nolic hydrogen chloride, provides the thiaZole Ia.
`
`SCHEME 1.
`
`1) nBuLi
`2) so2
`3) NCS
`
`—>
`
`Q1502
`
`1)
`
`OH
`
`| \
`/
`N
`
`goc
`
`5
`
`NH2
`
`OH
`
`H
`
`[iA/NVU
`
`/
`N
`
`P.
`Scheme 1 for thiaZoles Ia, 4-bromothiobenZamide
`Papadopopoulos, J. Org. Chem. 1976, 41, 962) is condensed
`With the appropriate chloroketone 2, typically by heating in
`ethanol at re?ux for 6 to 24 hours, to give bromophenylthi
`aZole 3. Treatment With n-butyllithium, conveniently in
`tetrahydrofuran at —78° C., folloWed by sulfur dioxide, With
`Warming to ambient temperature, provides the resultant
`lithium sul?nate. This may be readily converted to the
`corresponding sulfonyl chloride 4 by treatment With a chlo
`rinating agent such as N-chlorosuccimide. The protected
`
`(Ia)
`
`60
`
`The chloroketones 2 are commercially available, knoWn
`in the literature, or readily prepared by methods commonly
`knoWn to those skilled in the art. Conveniently, the corre
`65 sponding acid chloride 6 is treated With diaZomethane
`folloWed by hydrogen chloride to provide chloroketone 2, as
`illustrated in Scheme 2.
`
`SAWAI EX. 1010
`Page 7 of 21
`
`

`

`13
`
`SCHEME 2.
`
`o
`
`C1
`
`1) CHZNZ
`X—<‘9\ 2)HC1
`(R15
`
`6
`
`6,011,048
`
`14
`ThiaZoles Ib are prepared as illustrated in Scheme 4.
`Thioarnide 8 is treated With the appropriate
`2-brornoaldehyde 9 at elevated temperatures, conveniently
`in an inert solvent such as acetonitrile or acetonitrile/
`chloroforrn mixtures at re?ux temperature, to provide, after
`deprotection as described above, thiaZole Ib.
`
`o
`
`4>~X—( : t
`
`<31
`
`(RIB
`
`2
`
`An alternate approach for the synthesis of thiaZoles la is
`illustrated in Scheme 3. Nitrile 7 (Fisher, et. al., US. Pat.
`No. 5,561,142, Oct. 1, 1996) is converted to the correspond
`ing thiarnide by treatment With hydrogen sul?de in the
`presence of base such as triethylarnine. The thiaZole is
`formed from chloroketone 2 as described above. Removal of
`the t-butoXycarbonyl (Boc) protecting group by treatment
`With acid such as tri?uoroacetic acid in dichlorornethane or
`rnethanolic hydrogen chloride provides the desired thiaZole
`(Ia).
`
`OH
`
`Eoc
`
`\
`
`/
`N
`
`SCHEME3.
`
`0
`ll
`s
`N/u
`|
`o
`H
`
`7
`
`OH
`
`Eoc
`\ “CL 0 ll
`S
`/
`N
`MI
`|
`o
`H
`
`8
`
`2) TFA/CHZClZ
`
`OH
`
`H O” \Nl VU/
`
`(Ia)
`
`HZS
`—> Et3N, pyridine
`
`CN
`
`NH2
`
`SAWAI EX. 1010
`Page 8 of 21
`
`

`

`6,011,048
`
`16
`
`OH
`
`Boc
`
`SCHEME 4.
`
`o
`
`|
`H
`
`)
`
`Br
`
`X
`
`2) TFA/CH2C12
`
`OH
`
`Ell
`
`N
`
`H
`
`(Ib)
`
`S
`
`Bromoaldehydes 9 are known in the literature or readily
`prepared by methods comonly known to those skilled in the
`art. Conveniently, the corresponding alcohol 10 is oXidiZed
`to aldehyde 11, for example by treatment With
`o-iodoXybenZoic acid in DMSO (Frigerio and Santagostino,
`Tetrahedron Lett. 1994, 35, 8019). Bromination may be
`accomplished by treatment With a brominating agent, con
`veniently t-butyldimethylsilyl bromide/DMSO (Bellesia, et.
`al., J. Chem. Research (S) 1986, 428), to provide the desired
`bromoaldehydes 9.
`
`SCHEME 5.
`
`0
`1
`
`O:/—X 3 YR
`
`TBS—Br, DMSO
`acetonitrile, 00 C.
`
`11
`
`Br
`
`9
`
`ThiaZoles Ic are synthesiZed as outlined in Scheme 6. The
`appropriate nitrile 12, Which is commercially available,
`knoWn in the literature, or readily synthesiZed by methods
`knoWn to those skilled in the art, is treated With hydrogen
`sul?de in the presence of a base such as triethylamine, and
`the resultant thioamide is treated With ot,4
`dibromoacetophenone (13) at elevated temperature, conve
`niently in re?uxing ethanol, to provide thiaZole 14. This
`compound is then protected at the 5 -position, for eXample as
`the 5-trimethylsilyl derivative by treatment With
`n-butyllithium folloWed by trimethylsilyl chloride. Conver
`sion of the resultant bromo derivative 15 to the correspond
`ing sulfonyl chloride folloWed by sulfonamide formation
`With aniline 5 and removal of the Boc protecting group With
`TFA occurs as described above for Scheme 1. The silyl
`group is then removed, conveniently by treatment With
`hydrogen ?uoride in acetonitrile, to provide the desired
`thiaZole Ic.
`
`35
`
`40
`
`45
`
`55
`
`SAWAI EX. 1010
`Page 9 of 21
`
`

`

`6,011,048
`
`SCHEME 6.
`Br
`
`1) H25, Et3N
`NC—X—®\ R1
`()m 2) Br
`
`I
`
`1) nBuLi —>
`N
`\> X_@\ 2)TMs—c1
`5
`(R511.
`
`12
`
`B
`
`14
`
`13
`
`0
`
`Br
`
`1) nBuLi
`2>SO2
`3)NCS
`
`X—@\
`
`(R511.
`
`l
`
`N
`\
`5
`
`15
`
`Me3Si
`
`(31502
`
`I
`
`MeSSi
`
`N\
`>—X—@\(Rl)
`
`In
`
`s
`
`16
`
`OH
`
`N
`
`\
`N
`
`Eoc
`
`1)
`
`OH
`
`\
`| /
`N
`2)TFA CH2C12
`3) HF—acetonitrile
`
`_
`
`5
`
`NH2
`
`/S
`N |
`o
`
`H
`
`| “Me
`
`(RIB
`
`S
`
`ThiaZoles Id may be prepared as illustrated in Scheme 7.
`Aminoacetophenone 18 is prepared from bromo derivative
`13 using a modi?ed Delepine reaction (Goddard, C. J. J.
`Heterocyclic Chem. 1991, 28, 17), by treatment of com
`pound 13 With heXamethylenetetramine 17 followed by
`hydrochloric acid in methanol. Amine 18 is then treated With
`the appropriate acid chloride to give ketone 20. Formation of
`the thiaZole is accomplished by treatment With LaWesson’s
`
`45
`
`reagent at elevated temperature, conveniently in re?uxing
`toluene. The resultant bromo derivative 21 is converted to
`the desired thiaZole Id as described above in Scheme 1 for
`thiaZole Ia.
`
`Acid chlorides 19 are commercially available, knoWn in
`the literature, or readily prepared using methods commonly
`knoWn to those skilled in the art.
`
`Br
`
`SCHEME7.
`
`1) (NT ( N
`
`N\\// 17
`
`Br
`
`Br
`
`13
`
`18
`
`—
`
`SAWAI EX. 1010
`Page 10 of 21
`
`

`

`6,011,048
`
`-continued
`Br
`
`LaWesson's
`reagent
`PhCH3
`
`—>
`
`Br
`
`OO
`
`Ni
`
`H
`
`20
`
`X
`
`: \<R1>m
`
`c1502
`
`1)
`
`OH
`
`\
`
`|
`
`/
`N
`2) TFA—CH2Cl2
`3) HF—acetonitrile
`
`1
`(R )m
`
`I
`
`S
`
`N
`
`22
`
`OH
`
`Z
`
`/
`
`5
`I / X
`
`N:
`
`c \<R1>m
`
`1) nBuLi
`2) 502
`3) NCS
`
`21
`
`goc
`
`5
`
`NH2
`
`S
`
`| we N
`
`(RIB
`
`In some cases, the product I from the reactions described
`in Schemes 1—7 may be further modi?ed, for example, by
`the removal of protecting groups or the manipulation of
`substituents on R1. These manipulations may include, but
`are not limited to, reduction, oxidation, alkylation, acylation,
`and hydrolysis reactions Which are commonly knoWn to
`those skilled in the art.
`Compounds of Formula I contain one or more asymmetric
`centers and can thus occur as racemates and racemic
`mixtures, single enantiomers, diastereomeric mixtures and
`individual diastereomers. The present invention is meant to
`comprehend all such isomeric forms of the compounds of
`Formula I.
`Some of the compounds described herein contain ole?nic
`double bonds, and unless speci?ed otherwise, are meant to
`include both E and Z geometric isomers.
`Some of the compounds described herein may exist as
`tautomers such as keto-enol tautomers. The individual tau
`tomers as Well as mixture thereof are encompassed With
`compounds of Formula I.
`Compounds of the Formula I may be separated into
`diastereoisomeric pairs of enantiomers by, for example,
`fractional crystallization from a suitable solvent, for
`example methanol or ethyl acetate or a mixture thereof. The
`pair of enantiomers thus obtained may be separated into
`individual stereoisomers by conventional means, for
`example by the use of an optically active acid as a resolving
`agent.
`Alternatively, any enantiomer of a compound of the
`general Formula I or Ia may be obtained by st